Mechanisms of deep brain stimulation in the Nucleus Accumbens are unknown. Electrical stimulation of this region is complex, activating all cells within the region of stimulation as well as excitatory and modulatory afferents. Therefore, it is necessary to specifically parse out effects on individual cells within the region. To determine the effect of stimulation on cells within the NAc, cell-type specific activation of MSNs was performed by using an adeno-associated virus expressing ChR2 in NAc D1-MSNs of Dynorphin-Cre/Tdtomato mice. D1- and D2-MSNs are known to release different peptides locally and at efferent projections. Results indicate Substance P, exclusively expressed in D1-MSNs, may contribute to the behavioral effects of stimulation. To probe excitatory transmission, slices are prepared and whole-cell patch clamp is performed on D1-MSNs and D2-MSNs under fluorescent guidance. Excitatory input is electrically evoked prior to and following 50Hz (high frequency) optogenetic stimulation. Stimulation of D1-MSNs significantly depresses excitatory transmission on D1-MSNs, but potentiates excitatory transmission on D2-MSNs. Blocking the main receptor for Substance P, NK1 receptors, blocks potentiation on D2-MSNs and induces synaptic excitatory depression to the same degree as the stimulation-induced depression on D1-MSNs. Substance P (50nM) application mimics this potentiation effect on D2-MSNs in the NAc in a striatal dorsolateral to ventromedial gradient. These results suggest activation of NK1 receptors and Substance P release mediates the excitatory potentiation produced by stimulation. Furthermore, these effects are exclusively post-synaptic. Interestingly, using in situ hybridization, NK1 receptor expression is almost exclusively found in interneurons and all cholinergic interneurons express NK1 receptors. This suggests a disynaptic effect through cholinergic interneurons, may mediate the effect of Substance P on neuronal transmission. Indeed, high frequency but not low frequency stimulation causes elevated firing of cholinergic interneurons for up to 15 min following stimulation. Additionally only a single 5 sec train of HFS is necessary to produce elevated cholinergic interneuron firing and excitatory potentiation. Excitatory potentiation on D2-MSNs is muscarinic 1 receptor dependent signifying increased acetylcholine release is necessary for this effect. In these experiments, I demonstrate for the first time D1-MSNs can drive excitatory transmission on D2-MSNs. These results are significant in several ways: 1) D1-MSNs can drive excitation of cholinergic interneurons 2) High frequency stimulation or strong D1-MSN activation can rebalance output of MSN subtypes. Because MSN subtypes often oppositely mediate reward related outcomes (e.g., D1-MSNs promote reward while D2-MSNs blunt reward), we predict this stimulation can blunt opioid-mediated reward. Future experiments will test the potential effect of D1-MSN high frequency stimulation on reward. Additionally, current experiments are examining how stimulation releases Substance P in vivo using microdialysis and in vivo imaging to determine if afferent stimulation can drive Substance P release.